Genetic modifiers of mammary tumor susceptibility

乳腺癌是一种复杂的疾病，环境和遗传因素都会导致个人患乳腺癌的风险 发展中的疾病。TP53基因的可遗传突变与Li-Fraumeni综合征有关，在该综合征中， 癌症是最常见的肿瘤。Li-Fraumeni综合征的小鼠模型也显示出频繁的乳腺肿瘤， 但这取决于遗传背景。BM-BLC-TrP53*‘~小鼠乳腺肿瘤发生率的差异 (易感)和C57BU6-Trp5y‘~小鼠(抗病)使我们能够研究改变 对乳腺肿瘤的易感性。我们已经证明了隐性作用易感性和显性作用敏感性 等位基因与乳腺肿瘤易感性有关。作为乳房抑制因子的隐性作用的基因座 肿瘤(SuprMaml)已被定位于小鼠7号染色体的10Mb区域。相比之下，重组 通路介导的TrP53杂合性丢失在乳腺肿瘤中是遗传的显性性状。因此， Balb/c等位基因似乎干扰了DNA双链断裂同源定向修复的速率或保真度。这些 观察提供了一种识别影响小鼠乳腺肿瘤易感性的基因和途径的方法。 目的1：Dmbtl抑制乳腺肿瘤作用的分析。目的1.1：Dmbtl的作用 作为一种肿瘤抑制基因将被检测。将表达载体引入乳腺上皮细胞 将对细胞系和肿瘤发生率的变化进行监测。目的1.2：DMBT1蛋白在正常人中的表达 乳腺组织和肿瘤将被确定为评估DMBT1作为生物标志物的价值。 具体目的2：乳腺超微结构基因座对乳腺肿瘤发病率影响的遗传学解剖。目标 2.1：SuprMaml基因座的肿瘤抑制作用对乳腺癌发病率的影响程度将 在同源基因小鼠身上进行测定。目标2.2：间隔将在不同的同源基因小鼠中细分以进行细化 肿瘤抑制活性的位置。 具体目标3：分析改变DNA双链断裂修复速率的显性作用修饰物。 遗传背景可能通过改变DNA修复的速率或保真度来影响乳腺癌的易感性。 因此，DNA双链断裂修复的速度将使用合成底物进行监测。 识别改变乳腺癌易感性的基因将为风险评估提供标志 治疗干预的新靶点。

Breast cancer is a complex disease with both environmental and genetic factors contributing to an individual's risk of developing disease. Heritable mutations in TP53 have been associated with Li-Fraumeni syndrome in which breast cancer is the most common tumor. Mouse models of Li-Fraumeni syndrome also exhibit frequent mammary tumors, butdepends onthe geneticbackground. The differencein incidenceof mammarytumors betweenBM-Blc-Trp53*'~ mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammarytumors. We havedemonstrated that bothrecessive-acting anddominant-acting susceptibility alleles contribute to mammary tumor susceptibility. A recessive-acting locus that acts as a suppressor of mammary tumors (SuprMaml) has been mapped to a 10 Mb region of mouse chromosome 7. In contrast, a recombination pathway mediated loss of heterozygosity at Trp53 inmammarytumors andwas inherited as adominant trait. Therefore, BALB/c alleles appear to interferewith rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathwaysthat influence susceptibility to mammary tumors in mice. SpecificAim 1:Analysis of the effect of Dmbtlinsuppression of mammarytumors.Aim1.1: The effects ofDmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines andchanges intumor incidence will bemonitored. Aim 1.2: Expressionof DMBT1 protein innormal human breast tissues and tumors will be determined to assess the value of DMBT1 as a biomarker. Specific Aim 2: Genetic dissection of the effects ofthe SuprMaml locus on incidence of mammary tumors. Aim 2.1: The magnitude of the tumor suppressive effect of the SuprMaml locus on incidence of mammary tumors will be determined using in congenic mice. Aim 2.2: The interval will be subdivided in separate congenic mice to refine the location of the tumor suppressor activity. Specific Aim 3: Analysis of dominant-acting modifiers that alter rates of repair of DNA double strand breaks. Genetic background may influence susceptibility to mammarytumors byaltering the rates or fidelity of DNArepair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identificationofgenes thatmodifysusceptibilitytomammarytumors willprovidemarkers for riskassessment andnovel targets for therapeutic intervention.